Recent Advances in Kidney Cancer Treatment

1
Recent Advances in Kidney Cancer Treatment

• Nancy A. Dawson M.D.
• Professor of Medicine
• Director, Genitourinary Oncology Program
• Marlene and Stewart Greenebaum Cancer Center
• Baltimore, Maryland

2
Renal Cell Carcinoma

• Approximately 39,000 new cases diagnosed in US
  and 13,000 deaths in 2006. Worldwide, 95,000
  death annually.
• Kidney cancer has increased by 38 from 1974 to
  1990
• About 30 cases present with unresectable
  disease.

3

• MaleFemale ratio 21.
• Principally age 50-80.
• Familial form, von Hippel-Lindeau disease.
• Flank mass, hematuria, pain.
• Risk factors linked to cigarette smoking,
  obesity and hypertension

4
Treatment for RCC

• Surgery the only modality that appears to offer
  cure in RCC.
• Radiation palliative for metastases.
• Chemotherapy low response rate (lt10)
• Immunotherapy 20-30 response,5 durable CRs
  with high dose IL-2
• Targeted Therapy Prolonged PFS/OS !!

5
Clear cell RCC is characterized by VHL gene
inactivation

• VHL gene inactivation in clear cell renal
  carcinoma selected series

No significant VHL gene mutation (1 2/136) or
methlyation (2 3/135) observed in non-clear
cell RCC
Rini BI et al. J Clin Onc In press
6
RCCTargets of Single Agents

HIF
Bevacizumab
Erlotinib
TGF-a
VEGF
PDGF
VEGFR
EGFR
PDGFR
Sunitinib, Sorafenib, AG-013736
Sorafenib
Sorafenib
RAF
RAF
Kaelin WG. Nat Rev Cancer. 20022673-682.
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Bevacizumab (Avastin)

• Humanized monoclonal anti-VEGF antibody
• Binds and neutralizes all biologically active
  forms of VEGF
• Inhibits angiogenesis in experimental models
• Inhibits human xenograft tumor growth in vivo but
  not in vitro

Kim KJ, et al. Nature. 1993362841-844. Gordon
MS, et al. J Clin Oncol. 200119843-850.
8
Bevacizumab in RCC
PLACEBO Q 2 WEEKS (n40)
RANDOMIZE
PD
Treatment-refractory, metastatic RCC
BEVACIZUMAB (3 MG/KG) Q 2 WEEKS (n37)
BEVACIZUMAB (10 MG/KG) Q 2
WEEKS (n39)
Yang JC et al. NEJM 349(5), 2003
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Bevacizumab in RCC
Placebo Low-dose High-dose
Bevacizumab Bevacizumab
Response rate 0 0
10 TTP (months) 2.5 3.0
4.8 OS (months)
13.0 15.1
15.5
p0.041 vs. placebo p lt 0.001 vs.placebo
Yang JC et al. NEJM 349(5), 2003
10
CALGB 90206 A Randomized Phase III Trial of
Interferon Alpha-2b or Interferon Alpha-2b Plus
Bevacizumab in Advanced Renal Carcinoma
RANDOMIZE
IFNA 9 MU TIW
STRATIFY
UNTREATED, METASTATIC CLEAR CELL RCC
IFNA 9 MU TIW Bevacizumab 10
mg/kg IV q d1 and d15

• Patients will be stratified for nephrectomy
  status and Motzer risk group (0, 1-2 or 3 risk
  factors).

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Survival by the Memorial Sloan-Kettering Cancer
Center Risk Factor Model

• Risk factors are
• no prior nephrectomy
• KPS lt 80
• low HGB
• high corrected calcium
• high LDH

0 risk factors (164 patients, 30 alive) 1 or 2
risk factors (348 patients, 23 alive) 3, 4, or 5
risk factors (144 patients, 1 alive)
Proportion Surviving
Years Following Systemic Therapy
Lam JS, et al. J Urol. 20051731853-1862.
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AVOREN An International Phase III Trial of
Interferon Alpha-2a or Interferon Alpha-2a Plus
Bevacizumab in Advanced Renal Carcinoma
RANDOMIZE
IFN-alpha-2a
STRATIFY
UNTREATED, ADVANCED RCC N649
IFN-alpha-2a Bevacizumab 10
mg/kg IV q 2 weeks

• 12/06 Planned interim analysis showed improved
  PFS for the combination, DSMB recommended
  unblinding of study and all patients offered
  Avastin

13
Therapeutic inhibition of VEGF in RCC receptor
blockade (SU11248/Sunitinib)

• Oxindole TK inhibitor
• Orally bioavailable small molecule
• Selective multitargetinhibition of
• PDGF-R
• VEGF-R
• Kit
• Flt-3
• Plasma half-life ? 40 hours

CH3
O
H3C
CH3
N
N
H
CH3
F
N
H
O
N
H
Mendel et al. Clin Cancer Res 9, 2003
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SunitinibPhase 2 Studies

• Design
• Two single-arm, multicenter phase 2 trials
• End points response rate, time-to-progression
  (TTP), survival, and safety
• Treatment
• Treatment regimen 50 mg daily oral therapy given
  in repeated 6-week cycles of 4 weeks on 2
  weeks off
• Trial 1 (n63)
• Trial 2 (n106)
• Study ongoing, results as of the 4th
  International Kidney Cancer Symposium in October
  2005.

Motzer RJ, et al. Presented at 4th International
Kidney Cancer Symposium of the Kidney Cancer
Association, October 21-23, 2005 Chicago, IL.
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Sunitinib Phase 2 Studies Best Response by
RECIST
1 patient with change in cancer diagnosis
excluded from analysis
Motzer RJ, et al. Presented at 4th International
Kidney Cancer Symposium of the Kidney Cancer
Association, October 21-23, 2005 Chicago, IL.
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Progression-Free Survival Trials 1 and 2 Combined
1.0
0.9
Median PFS Trial 1 8.7 monthsTrial 2 8.1
months Combined 8.2 months (95 CI 7.8, 10.4)
0.8
0.7
0.6
Proportion of Patients Progression-Free
0.5
0.4
0.3
0.2
0.1
0
0
9
15
18
24
3
6
12
21
27
Sunitinib Therapy (Months)
Motzer RJ, et al. Presented at 4th International
Kidney Cancer Symposium of the Kidney Cancer
Association, October 21-23, 2005 Chicago, IL.
17
SU11248 Phase II Clinical Results
Baseline
After 4 weeks of SU11248
After 8 weeks of SU11248
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Sunitinib Phase 2 Studies Treatment-Related
Adverse Events
Motzer RJ, et al. Presented at 4th International
Kidney Cancer Symposium of the Kidney Cancer
Association, October 21-23, 2005 Chicago, IL.
19
Phase III trial of IFNA vs Sunitinib
Untreated, metastatic RCC (n750)
Sunitinib(50 mg/day x4weeks q 6 weeks)
IFNA 9 MU TIW

• Response rate 6 (Plt0.001)
  31
• PFS (months) 5 (Plt0.001) 11
• OS (months)

Motzer R et al. NEJM 2007356115-124
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Sorafenib

• Sorafenib selectively inhibits B-RAF, VEGFR-2,
  VEGFR-3, PDGFR-b, FLT-3, and c-KIT
• Originally identified through inhibitory effects
  on RAF-1, a serine-threonine kinase
• Inhibits angiogenesis in experimental models
• Inhibits growth of human renal cell carcinoma,
  melanoma, colon, breast, ovarian, and non-small
  cell lung cancer xenografts
• NEXAVAR FDA approved 12/05 for advanced Renal
  Cell cancer

Riedl B, et al. Proc Am Soc Clin Oncol.
20012083a.Wilhelm S, et al. Cancer Res.
20046470997109.
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Randomized Discontinuation TrialPatient Outcome
gt25 Tumorshrinkage
Continue sorafenib
16 (50) SD at 24 weeks
Continue sorafenib 12 weeks
-25 to 25Tumor stabilization
Sorafenib 12-week run-in
Placebo 12 weeks
6 (18) SD at 24 weeks
gt25Tumor growth
Off study
SD Stable Disease Ratain MJ, et al. ASCO 2005,
abstract 4544.
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Randomized Discontinuation TrialProgression-Free
Survival (PFS)
1.00
Censored
Sorafenib
(n32)
0.75
Placebo (n33)
Median PFS from randomization Placebo 6
weeks Sorafenib 24 weeks p 0.0087
Survival Distribution Function
0.50
0.25
0.00

84
0
50
100
150
200
250
300
350
450
400
Days from Randomization
Ratain MJ, et al. ASCO 2005, abstract 4544.
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Treatment Approaches in Renal Cancer Global
Evaluation Trial (TARGETs)Study Design and
Objectives

• Eligibility criteria
• Histologically/cytologically confirmed,
  unresectable and/or metastatic disease
• Clear cell histology
• Measurable disease
• Failed one prior systemic therapy in last 8
  months
• ECOG PS 0 or 1
• Good organ function
• No brain metastasis
• Poor-risk MSKCC group excluded

(11) Randomization N903
Sorafenib400 mg bid

• Major end points
• Survival (a0.04)
• PFS (a0.01)

Placebo

• Stratification
• MSKCC criteria
• Country

Escudier B, et al. NEJM 2007356125-134.
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Objective Responses by Investigator Assessment
Number of Patients ()
Sorafenib (n451)
Placebo (n452)
Best Response (RECIST)
Complete Response (CR) 1 (lt1) 0
(0) Partial Response (PR) 43 (10) 8
(2) Stable Disease (SD) 333 (74) 239
(53) Progressive Disease (PD) 56 (12) 167
(37) Missing 18 (4) 38 (8)
Patients randomized at least 6 weeks before
data cut-off of May 31, 2005
Escudier B, et al. NEJM, 200735615-134. .
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TARGETsProgression-Free Survival Benefit
Sorafenib
Placebo
Censored observation
Median PFS Sorafenib 5.5 months Placebo 2.8
months Hazard ratio (S/P) 0.51
Proportion of Patients Progression-Free
Time from Randomization (Months)
Based on investigator assessment
Escudier B, et al. Presented at ECCO 13 the
European Cancer Conference, October 30-November
3, 2005 Paris, France. abstract 794.
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TARGETsMedian Overall Survival
Escudier B, et al. NEJM, 200735615-134.
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Incidence of Treatment-Emergent Adverse Events
in ?2 patients
Sorafenib (n451)
Placebo (n451)
Grades 3/4
Grades 3/4
Any grade
Any grade
Decreased hemoglobin 34 (8) 12 (3) 33
(7) 20 (4)
Hypertension 76 (17) 16 (4) 8 (2) 2
(lt1)
Fatigue 165 (37) 22 (5) 125 (28) 16 (4)
Diarrhea 195 (43) 11 (2) 58 (13) 3 (1)
Handfoot skin reaction 134 (30) 25 (6) 30
(7)
Tumor pain 29 (6) 13 (3) 24 (5) 8
(2) Bone pain 34 (8) 3 (1) 35
(8) 15 (3)
Dyspnea 65 (14) 16 (4) 52 (12) 11 (2)
NCI-CTC Version 3.0
Escudier B, et al. Presented at ECCO 13 the
European Cancer Conference, October 30-November
3, 2005 Paris, France. abstract 794.
28
Hand-Foot Syndrome
Grade 3 Hand-foot syndrome
Improved to Grade 1
Sorafenib 400 mg bid. Image courtesy of Laura
Wood, RN, MSN, OCN.
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CCI-779 (temsirolimus)

• Water-soluble ester of sirolimus
• Novel mammalian target of rapamycin (mTOR) kinase
  inhibitor
• Exhibits immunosuppressive and anti-tumor
  activity
• Reduces tumor growth in PTEN /- mice

Podsypanina K, et al. PNAS. 20019810320-10325. L
icun W, et al. Cancer Res. 2005652825-2831.
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Phase 3 Study of TEMSR and IFN in Advanced RCC

• 626 patients with advanced metastatic RCC with
  poor-risk features
• 209 sites (26 countries)

• Geographic Regions
• WEU AU CA (22)
• US (30)
• EEU Other (48)
• Nephrectomy
• Yes (67)
• No (33)

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Overall Survival by Treatment Arm
Arm 2 Temsirolimus
Probability of Survival
Arm 1 IFN
Arm 3 IFN Temsirolimus
Time from Randomization, Months
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Other Efficacy Endpoints
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Intergroup Adjuvant TrialArms/RegimensPatients
minimum 6 weeks post radical nephrectomy will be
randomized to receive Arm A Nexavar 400mg po BID
versus Arm B Sutent 50 mg qd for 28days q 6weeks
vs Arm C placebo, All for 12 months

• Stratify
• Disease Stage
• II T2 Grade 3,4
• III T1,N1, M0
• T2,N1,M0
• T3aN0-1, M0
• T3bN0-1,M0
• T3cN0-1,M0
• IV T4 anyN M0
• AnyT, N2,M0
• Histologic Subtype
• Clear cell
• Non-clear cell
•  

Arm A Sorafenib (Nexavar)
Randomize
Arm B Sunitinib (Sutent)
Arm C Placebo
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Proposed Treatment Options2007
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Thank You